1. Field of the Invention
The present invention is broadly directed to an improved method for synthesizing indolylmaleimides, particularly bisindolylmaleimides, and especially non-symmetrical bisindolylmaleimides. In a more particular aspect, the present invention relates to an improved method of producing these indolylmaleimides using organometallic chemistry. In yet other aspects, the present invention is directed to a novel intermediate useful for preparing bisindolylmaleimides and to a novel intermediate step in the synthesis of bisindolylmaleimides.
2. Description of Related Art
Protein kinase C (PKC), and particularly its various isozymes, have been associated with a variety of disease states including cancer, central nervous system disorders, Alzheimer's, cardiovascular disease, dermatological diseases, inflammation, autoimmune diseases such as rheumatoid arthritis, and diabetic complications. As a result, there is a high level of research aimed at identifying therapeutic agents for inhibiting PKC activity as a way of treating these various conditions, and especially PKC inhibitors that are isozyme selective. Substituted indolylmaleimides, and particularly substituted bisindolylmaleimides, are one major class of compounds which have been found to be selective PKC inhibitors. (Steglich et al., Angew. Chem. Int. Ed. Engl. (1980), 19, 459). A wide variation of substituted bisindolylmaleimides are known in the art. Compounds based on such bisindolylmaleimides wherein the indolyl nitrogens are linked together through various moieties also have shown promise as selective PKC inhibitors. As a result, the prior art has describe a wide variety of such compounds and major investigations are directed to these materials.
A variety of approaches have been reported in the literature for synthesizing such indolylmaleimides (Bit et al., J. Med. Chem., 36:21-29 (1993); Bit et al., Tetrahedron Lett, 34: 5623 (1993); Bergman et al., Tetrahedron Lett., 28:4441-4444 (1987); Davis et al., Tetrahedron Lett., 31:2353 (1990); Davis et al., Tetrahedron Lett., 31:5201-5204 (1990); and Brenner et al., Tetrahedron Lett., 44: 2887-2892 (1988)). Nevertheless, the art continues to look for additional approaches that permit higher yields, easier (e.g. milder) reaction conditions, less complicated process steps, a broader range of potential substituents and the like.
One of the more commonly used approaches for preparing bisindolylmaleimides, generally described by this literature, involves the condensation of an indole-1-Grignard reagent with a dihalomaleimide according to the following: ##STR1##
Generally, this reaction is carried out in an inert solvent such as benzene, toluene, tetrahydrofuran or ether at a temperature between room temperature and reflux temperature of the reaction mixture. The indole Grignard reagent is preferably prepared in situ from the indole and an alkyl magnesium halide such as ethyl magnesium bromide or ethyl magnesium iodide in a manner known in the art.
The reaction depicted above has been found to be dependent on solvent conditions. When carried out in a toluene:THF:ether solvent system this reaction provides the bisindolylmaleimide in greater than 80 percent yield and greater than 95 percent purity. Monosubstituted maleimides also can be produced by this approach, potentially permitting the eventual synthesis of non-symmetrical bisindolylmaleimides.
A major problem with this general approach, however, is its limited applicability for synthesizing a variety of substituted bisindolylmaleimides. In particular, this approach can not be used with 1-substituted indole starting materials and thus is not easily adapted to the preparation of N-substituted indolylmaleimides.
The present invention is based on the discovery of a particularly simple approach to the synthesis of optionally substituted indolylmaleimides and especially the synthesis of symmetrical, as well as non-symmetrical, N-substituted bisindolylmaleimides using a palladium catalyst. Under preferred conditions, the desired compounds can be produced in acceptably high yields.